A rare tonsillar metastasis of Merkel cell carcinoma: A case report

Abstract Merkel cell carcinoma (MCC) metastasis to the tonsil is extremely rare with five published cases. We report the case of a patient with palatine tonsillar MCC metastasis, who presented without oropharyngeal symptoms, which contrast prior reported cases.


| INTRODUCTION
Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine tumor that commonly presents as cutaneous or mucosal tumor, arising from Merkel mechanoreceptor cells in the skin and in ectoderm-derived mucosa. 1,2 MCC has been reported to have a rising incidence rate of 95% from 2000 to 2013. 3 Despite the early detection and optimal control with surgical and adjuvant radiotherapy for Stage I-III disease, the overall survival rate is between 30% and 75%. 4,5 MCC development is associated with Merkel cell polyomavirus (MCPyV) in 80% of cases and chronic UV-mediated damage in 20% of cases, and commonly seen among people older than 50 years. 6,7 Studies have identified the most frequently affected areas to be the head and neck region (50%), trunk (30%) and the arms and legs (10%), and approximately 4.5% are of mucosal origin. 3,7 About 65%-70% of patients with MCC present with localized disease to the skin, 25% have regional lymphadenopathy, and 5%-8% have distant metastasis with the most common sites being the liver, lung, brain, and bone. 8,9 Adults are more likely than children to have MCPyV detectable by polymerase chain reaction in elective tonsillectomy specimens obtained for non-oncologic indications. 10 Despite this, tumor metastatic to the oral cavity is an infrequent occurrence, with metastasis to the palatine tonsil being an extremely rare event. 2,11 Considering all primary tumor types, only about 100 cases of metastases to the palatine tonsil have been documented in the literature, specifically with MCC metastatic to the palatine tonsil comprising of only five of the cases. 1,2 Among the reported cases of metastatic MCC to the palatine tonsil, patients commonly presented with pharyngitis, dysphagia, and other oropharyngeal symptoms, years after wide excision of the primary cutaneous tumor. 1,2,5 We report a case of a 57-year-old female patient who presented with primary MCC of the right buttock, with an incidental, asymptomatic metastasis to the left palatine tonsil.

| CASE PRESENTATION
An otherwise healthy 57-year-old female patient presented with a 3-year history of an enlarging right buttock soft tissue mass. The mass was not associated with pain; however, there was a history of minor trauma to the area. Physical examination revealed a right buttock cutaneous mass measuring 12 × 8 cm and a firm, non-tender right inguinal mass. Pre-referral computed tomography (CT) of the pelvis with IV contrast demonstrated a lobulated 8 cm right buttock mass and multiple enlarged right inguinal lymph nodes. Core needle biopsy of the buttock and fine needle aspirate of the inguinal mass demonstrated neuroendocrine carcinoma.
Immunohistochemical staining of the right buttock diagnostic biopsy specimen was performed, which was positive for CK20, chromogranin, EMA and Merkel cell polyoma virus and negative for thyroid transcription factor-1 (TTF-1) and CK7. These findings were consistent with the diagnosis of MCC. Further examination with MCPyV oncoprotein antibody test was obtained, revealing an antibody titer of 115,000 standard units. At our institution, fused fluorodeoxyglucose-18 positron emission tomography (PET)-CT scan noted asymmetric uptake involving the left tonsil region, concerning for neoplasm versus an inflammatory process ( Figure 1). She denied associated oropharyngeal symptoms and a firm left tonsil was noted on oral examination; there was no palpable cervical or supraclavicular lymphadenopathy.
Per the evidence-based 4 consensus recommendation of our multidisciplinary cutaneous tumor board, the patient underwent left tonsillectomy, right buttock wide local excision, and lymphadenectomy of her right inguinal, iliac, and obturator basins with sartorius muscle transposition flap coverage of the femoral vessels. Consideration was given to preoperative tonsillar biopsy, but this was not pursued due to the risk of bleeding and sampling error. Postoperatively, she was discharged in good condition after an uncomplicated 4-day inpatient stay. Evaluation of her surgical specimens demonstrated a 6.5 cm MCC of the right buttock with widely negative microscopic margins, mitotic index of 22 mitoses per mm 2 and lympho-vascular invasion; 1/16 lymph nodes involved; and metastatic MCC of the left tonsil ( Figure 2). One month later, she underwent a planned second-stage rotational flap closure of the gluteal resection defect. Her final pathologic staging was Stage IV (pT4N1bM1c) and she initiated a 1-year course of adjuvant therapy with avelumab 800 mg every 2 weeks. On follow-up visits, a decreasing trend in her MCPyV oncoprotein antibody titer was noted, as shown in Figure 3.
The patient is currently 11 months from the initial diagnosis of MCC of the right buttock, 10 months from her pathological diagnosis of metastatic MCC of the tonsil, and is without any evidence of disease progression based on physical examination and contrast-enhanced surveillance CT imaging. She continues her course of adjuvant avelumab therapy and is closely monitored for disease progression with regular follow-ups.

| DISCUSSION
Tonsillar neoplasm is a rare occurrence and metastasis is extremely rare, with 0.8% accounting for metastasis with extra-tonsillar primary. 12 Metastatic tonsillar tumors are uncommon due to the fact that the tonsil lacks afferent lymphatic vessels and histologically consists of mainly reticuloendothelial cells with strong ability to clear tumor. 13 Therefore, in this case, malignant dissemination to the tonsil is suggested to be by hematogenous route. 5 An alternative route would be retrograde via cervical lymphatics to the tonsil. 5,14 Colorectal carcinoma, breast cancer, lung cancer, gastric carcinoma, melanoma, and seminoma are the primary tumors that account for the majority of metastases to the palatine tonsil. 12 Metastatic involvement to the tonsil is typically metachronous and generally presents with odynophagia, pharyngitis, dysphagia, and globus. 13 The five prior reported cases of metastatic MCC to the palatine tonsil are metachronous (7 months to 7 years after presentation) and were all symptomatic. 1 In one study, the F I G U R E 1 Cross-sectional PET-CT images showing fluorodeoxyglucose accumulation in the right buttock (arrow in A), indicating the tumor, and asymmetric accumulation in the left tonsil (arrow in B), concerning for neoplasm or inflammatory process.

(A) (B)
authors used microarray-based comparative genomic hybridization to demonstrate that what appeared to be a metachronous metastasis to the tonsil was actually a second primary MCC. 15 In contrast, we report a patient presenting with a synchronous, asymptomatic palatine tonsillar metastasis that was incidentally discovered on staging PET-CT. MCC risk factors include chronic UV-mediated damage to sun-exposed areas of the skin and chronic immunosuppression due to HIV, lymphoma, or organ transplantation. 8 Microscopically, MCC has similar histopathological characteristics as small-cell carcinoma of the lungssmall, blue, round cells with prominent nuclei and scant cytoplasm, and must be excluded with a negative TTF-1 and CK7, which was noted in our case. 6,8 Other immunohistochemical staining that are helpful in differential diagnosis include: positive CD99 for primitive neuroectodermal tumor, leukocyte common antigen positive for small-cell lymphomas and S100, Melan-A and HMB-45 positive for malignant melanoma. 8 As a neuroendocrine tumor, neuroendocrine markers such as chromogranin A, synaptophysin, CD56, neuron-specific enolase usually confirm the diagnosis. 1,16 MCPyV involvement in MCC is demonstrable via tumor staining and serology (80% and 60%, respectively). 8 Though MCC in patients with elevated MCPyV oncoprotein antibody titers have a favorable survival compared to seronegative patients, and when detectable, the oncoprotein antibody titer can serve as a tumor marker indicative of overall MCC burden. 17 In this case, the serum MCPyV oncoprotein antibody was elevated at diagnosis and appropriately continues to decrease throughout the treatment course. The efficacy of immune checkpoint inhibition in patients with advanced MCC is thought to relate to the high tumor mutation burden, as the MCPyV status is not predictive of response to immunotherapy. 17

ACKNOWLEDGMENTS
This publication was made possible in part by support from the Kent State University Open Access Publishing Fund.

FUNDING INFORMATION
No funding source to be declared.

CONFLICT OF INTEREST STATEMENT
Authors have no conflict of interest to declare.

DATA AVAILABILITY STATEMENT
The data presented in this study are available in this article.

CONSENT
Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.